Predictors of genetic diagnosis in individuals with developmental and epileptic encephalopathies

Maria Luiza Benevides; Helena T de Moraes; Diana M M Granados; Luciana C Bonadia; Letícia Sauma; Maria Augusta Montenegro; Marilisa M Guerreiro; Íscia Lopes-Cendes; Ana Carolina Coan

doi:10.1016/j.yebeh.2024.109762

Predictors of genetic diagnosis in individuals with developmental and epileptic encephalopathies

Epilepsy Behav. 2024 Apr 17:155:109762. doi: 10.1016/j.yebeh.2024.109762. Online ahead of print.

Authors

Maria Luiza Benevides¹, Helena T de Moraes², Diana M M Granados³, Luciana C Bonadia⁴, Letícia Sauma⁵, Maria Augusta Montenegro⁶, Marilisa M Guerreiro⁷, Íscia Lopes-Cendes⁸, Ana Carolina Coan⁹

Affiliations

¹ Child Neurology Service, Department of Neurology, University of Campinas (UNICAMP), Campinas - São Paulo (SP), Brazil. Electronic address: benevidesmarialuiza@gmail.com.
² Department of Translational Medicine, UNICAMP, Campinas - SP, Brazil. Electronic address: helenatadiello@gmail.com.
³ Department of Translational Medicine, UNICAMP, Campinas - SP, Brazil. Electronic address: diamej@gmail.com.
⁴ Department of Translational Medicine, UNICAMP, Campinas - SP, Brazil. Electronic address: bonadia@unicamp.br.
⁵ Child Neurology Service, Department of Neurology, University of Campinas (UNICAMP), Campinas - São Paulo (SP), Brazil. Electronic address: lelesauma@gmail.com.
⁶ Rady Children's Hospital, University of California San Diego, San Diego, CA, USA. Electronic address: mam290610@gmail.com.
⁷ Child Neurology Service, Department of Neurology, University of Campinas (UNICAMP), Campinas - São Paulo (SP), Brazil; Brazilian Institute of Neuroscience and Neurotechnology, BRAINN, at UNICAMP, Campinas, SP, Brazil. Electronic address: marilisa.guerreiro@gmail.com.
⁸ Department of Translational Medicine, UNICAMP, Campinas - SP, Brazil; Brazilian Institute of Neuroscience and Neurotechnology, BRAINN, at UNICAMP, Campinas, SP, Brazil. Electronic address: icendes@unicamp.br.
⁹ Child Neurology Service, Department of Neurology, University of Campinas (UNICAMP), Campinas - São Paulo (SP), Brazil; Brazilian Institute of Neuroscience and Neurotechnology, BRAINN, at UNICAMP, Campinas, SP, Brazil; Neuroimaging Laboratory, UNICAMP, Campinas, SP, Brazil. Electronic address: acoan@unicamp.br.

PMID: 38636144
DOI: 10.1016/j.yebeh.2024.109762

Abstract

Objective: To evaluate the clinical predictors of positive genetic investigation in developmental and epileptic encephalopathies, beyond the influence of Dravet Syndrome.

Methods: The study included 98 patients diagnosed with developmental and epileptic encephalopathies. The patients underwent Sanger sequencing of SCN1A, Chromosomal Microarray Analysis, and Whole Exome Sequencing. The association of clinical variables with a positive genetic test was investigated using univariate and multivariate analysis.

Results: Genetic diagnosis was identified in 47 (48 %) patients with developmental and epileptic encephalopathies. Beyond Dravet Syndrome influence, first seizure in the context of fever (p < 0.01), seizures precipitated by temperature (p = 0.04), cognitive regression (p = 0.04), hypotonia (p < 0.01), and focal seizures (p = 0.03) increased the chances of a positive genetic investigation. In contrast, atonic seizures (p = 0.01) and generalized discharges on electroencephalogram (p = 0.02) decreased the chances. Dravet Syndrome was positively associated with a genetic developmental and epileptic encephalopathies etiology (p < 0.01), whereas epilepsy with myoclonic-atonic seizures (p = 0.01), developmental and epileptic encephalopathies with spike-wave activation in sleep (p = 0.04), and Lennox-Gastaut syndrome (p = 0.03) were negatively associated. In multivariate analysis, the first seizure in the context of fever (p < 0.01) and hypotonia (p = 0.02) were positively, and atonic seizures (p = 0.01) were negatively and independently associated with a genetic etiology.

Conclusion: The predictive variables of genetic investigation in developmental and epileptic encephalopathies are first seizure in the context of fever and hypotonia, whereas atonic seizures decrease the chances of finding a genetic cause for developmental and epileptic encephalopathies. Regarding epileptic syndromes, Dravet Syndrome is highly associated with a positive genetic test, whereas epilepsy with myoclonic-atonic seizures, developmental and epileptic encephalopathies with spike-wave activation in sleep, and Lennox-Gastaut syndrome are rarely associated with a positive genetic investigation.

Keywords: Epilepsy; Genetic; Neurodevelopmental disorders.